EP1713912B1 - Modifizierte sirna (short interfering rna) - Google Patents
Modifizierte sirna (short interfering rna) Download PDFInfo
- Publication number
- EP1713912B1 EP1713912B1 EP05700612.4A EP05700612A EP1713912B1 EP 1713912 B1 EP1713912 B1 EP 1713912B1 EP 05700612 A EP05700612 A EP 05700612A EP 1713912 B1 EP1713912 B1 EP 1713912B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- lna
- rna
- modified
- modified sirna
- sense strand
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 108020004459 Small interfering RNA Proteins 0.000 title claims description 110
- 239000004055 small Interfering RNA Substances 0.000 title description 2
- 239000000178 monomer Substances 0.000 claims description 137
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 85
- 108091081021 Sense strand Proteins 0.000 claims description 71
- 230000000692 anti-sense effect Effects 0.000 claims description 64
- 125000003729 nucleotide group Chemical group 0.000 claims description 53
- 239000002773 nucleotide Substances 0.000 claims description 49
- -1 pseudoisocytosine Chemical compound 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 28
- 235000000346 sugar Nutrition 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 21
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 21
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 18
- RHCSKNNOAZULRK-APZFVMQVSA-N 2,2-dideuterio-2-(3,4,5-trimethoxyphenyl)ethanamine Chemical group NCC([2H])([2H])C1=CC(OC)=C(OC)C(OC)=C1 RHCSKNNOAZULRK-APZFVMQVSA-N 0.000 claims description 14
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 11
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 230000014509 gene expression Effects 0.000 claims description 10
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 8
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
- 229930024421 Adenine Natural products 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 claims description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 4
- 229930010555 Inosine Natural products 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229960003786 inosine Drugs 0.000 claims description 4
- 229940113082 thymine Drugs 0.000 claims description 4
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 claims description 3
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 claims description 3
- HBJGQJWNMZDFKL-UHFFFAOYSA-N 2-chloro-7h-purin-6-amine Chemical compound NC1=NC(Cl)=NC2=C1NC=N2 HBJGQJWNMZDFKL-UHFFFAOYSA-N 0.000 claims description 3
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 claims description 3
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 238000012986 modification Methods 0.000 description 31
- 230000004048 modification Effects 0.000 description 31
- 108091034117 Oligonucleotide Proteins 0.000 description 30
- 230000000694 effects Effects 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 22
- 108020004414 DNA Proteins 0.000 description 19
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 19
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 19
- 201000011510 cancer Diseases 0.000 description 19
- 238000005859 coupling reaction Methods 0.000 description 18
- 230000008878 coupling Effects 0.000 description 16
- 238000010168 coupling process Methods 0.000 description 16
- 238000011282 treatment Methods 0.000 description 16
- 102000039446 nucleic acids Human genes 0.000 description 15
- 108020004707 nucleic acids Proteins 0.000 description 15
- 150000007523 nucleic acids Chemical class 0.000 description 15
- 229910019142 PO4 Inorganic materials 0.000 description 14
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 14
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 14
- 239000010452 phosphate Substances 0.000 description 14
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 230000009368 gene silencing by RNA Effects 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000002246 antineoplastic agent Substances 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 229940127089 cytotoxic agent Drugs 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 10
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 10
- 230000000295 complement effect Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 9
- 150000008300 phosphoramidites Chemical class 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 8
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 8
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 208000027866 inflammatory disease Diseases 0.000 description 7
- 125000001921 locked nucleotide group Chemical group 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 229940035893 uracil Drugs 0.000 description 7
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 6
- 108010092160 Dactinomycin Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 6
- 229960000473 altretamine Drugs 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 6
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 6
- 229960003171 plicamycin Drugs 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 230000004700 cellular uptake Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 102000015790 Asparaginase Human genes 0.000 description 4
- 108010024976 Asparaginase Proteins 0.000 description 4
- 108010006654 Bleomycin Proteins 0.000 description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 108010000817 Leuprolide Proteins 0.000 description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 4
- 108060004795 Methyltransferase Proteins 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 101710163270 Nuclease Proteins 0.000 description 4
- 108010016076 Octreotide Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 108700025316 aldesleukin Proteins 0.000 description 4
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 4
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 4
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 4
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 4
- 229960002436 cladribine Drugs 0.000 description 4
- 229940104302 cytosine Drugs 0.000 description 4
- 229960000640 dactinomycin Drugs 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 4
- 229960002340 pentostatin Drugs 0.000 description 4
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000002652 ribonucleotide group Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 4
- 230000014616 translation Effects 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 108090000331 Firefly luciferases Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000012124 Opti-MEM Substances 0.000 description 3
- 108010052090 Renilla Luciferases Proteins 0.000 description 3
- 108091028664 Ribonucleotide Proteins 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 102000004338 Transferrin Human genes 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000003197 gene knockdown Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002336 ribonucleotide Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229940104230 thymidine Drugs 0.000 description 3
- 239000012581 transferrin Substances 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- HBUBKKRHXORPQB-FJFJXFQQSA-N (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O HBUBKKRHXORPQB-FJFJXFQQSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- JUDOLRSMWHVKGX-UHFFFAOYSA-N 1,1-dioxo-1$l^{6},2-benzodithiol-3-one Chemical compound C1=CC=C2C(=O)SS(=O)(=O)C2=C1 JUDOLRSMWHVKGX-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-BIIVOSGPSA-N 2'-deoxythymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-BIIVOSGPSA-N 0.000 description 2
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 2
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 102100021906 Cyclin-O Human genes 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 241000254158 Lampyridae Species 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229910052770 Uranium Inorganic materials 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 229940098174 alkeran Drugs 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960001097 amifostine Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 229940078010 arimidex Drugs 0.000 description 2
- 229960003272 asparaginase Drugs 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229940108502 bicnu Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 229940088954 camptosar Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 229940088547 cosmegen Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 229940026692 decadron Drugs 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- 230000001066 destructive effect Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 229940073038 elspar Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229940000733 emcyt Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 229940098617 ethyol Drugs 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical group 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- 108020005243 folate receptor Proteins 0.000 description 2
- 102000006815 folate receptor Human genes 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 229940003183 hexalen Drugs 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 229940088013 hycamtin Drugs 0.000 description 2
- 229940096120 hydrea Drugs 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229940099279 idamycin Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 229940065638 intron a Drugs 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 229940063725 leukeran Drugs 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 229940087857 lupron Drugs 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 229940087732 matulane Drugs 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- ZDZOTLJHXYCWBA-BSEPLHNVSA-N molport-006-823-826 Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-BSEPLHNVSA-N 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- 229940087004 mustargen Drugs 0.000 description 2
- 229940090009 myleran Drugs 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940086322 navelbine Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229940109551 nipent Drugs 0.000 description 2
- 229940085033 nolvadex Drugs 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 229960002700 octreotide Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229940063179 platinol Drugs 0.000 description 2
- 108010089520 pol Gene Products Proteins 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940087463 proleukin Drugs 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229940117820 purinethol Drugs 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229940072272 sandostatin Drugs 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000006177 thiolation reaction Methods 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 239000001226 triphosphate Substances 0.000 description 2
- 235000011178 triphosphate Nutrition 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LMZHZBVAKAMCEG-FJGDRVTGSA-N 4-amino-1-[(2r,3r,4r,5r)-3-amino-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@](O)(N)[C@H](O)[C@@H](CO)O1 LMZHZBVAKAMCEG-FJGDRVTGSA-N 0.000 description 1
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 description 1
- GONFBOIJNUKKST-UHFFFAOYSA-N 5-ethylsulfanyl-2h-tetrazole Chemical compound CCSC=1N=NNN=1 GONFBOIJNUKKST-UHFFFAOYSA-N 0.000 description 1
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 1
- YSMTWZBIKDQUHK-UHFFFAOYSA-N CC(C)ON(OC(C)C)P(CCC#N)(O)O Chemical group CC(C)ON(OC(C)C)P(CCC#N)(O)O YSMTWZBIKDQUHK-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000009738 Connective Tissue Neoplasms Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010072449 Desmoplastic melanoma Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023849 Laryngeal papilloma Diseases 0.000 description 1
- 206010024218 Lentigo maligna Diseases 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 208000006431 amelanotic melanoma Diseases 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940037157 anticorticosteroids Drugs 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 208000016576 colorectal neuroendocrine tumor G1 Diseases 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical class CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;n,n-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 1
- 230000001819 effect on gene Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012909 foetal bovine serum Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000009000 laryngeal papillomatosis Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000011080 lentigo maligna melanoma Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000001906 matrix-assisted laser desorption--ionisation mass spectrometry Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000001293 nucleolytic effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940124276 oligodeoxyribonucleotide Drugs 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000004219 purine nucleobase group Chemical group 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000012536 storage buffer Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 208000030457 superficial spreading melanoma Diseases 0.000 description 1
- 208000014794 superficial urinary bladder carcinoma Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
- C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/33—Chemical structure of the base
- C12N2310/334—Modified C
- C12N2310/3341—5-Methylcytosine
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/51—Methods for regulating/modulating their activity modulating the chemical stability, e.g. nuclease-resistance
Definitions
- the present invention is directed to novel, modified siRNA which are significantly impaired in their ability to support cleavage of mRNA when incorporated into a RISC complex.
- modified siRNA may be useful as therapeutic agents, e.g., in the treatment of various cancer forms.
- RNA interference RNA interference
- Elegans were made by Fire et al. (Nature, 1998, 391, 806-811 ). Long stretches of double stranded RNA (dsRNA) was found to have a potent knock-down effect on gene expression that could last for generations in the worm. RNA interference (RNAi) rapidly became a functional genomic tool in C. Elegans (early RNA interference is reviewed by Fire (TIG, 1999,15, 358-363 ) and Bosher and Labouesse (Nature Cell Biology, 2000, 2, E31-E36 )).
- RNA interference was demonstrated to work in vertebrates were performed in zebrafish embryos and mouse oocytes ( Wargelius et al., Biochem. Biophys. Res. Com. 1999, 263, 156-161 , Wianny and Zernicka-Goetz, Nature Cell Biology, 2000, 2, 70-75 ). Since dsRNA induces non-specific effects in mammalian cells it has been argued that these mechanisms were not fully developed in the mouse embryonic system ( Alexopoulou et al., Nature, 2001, 413, 732-738 , Reviews: Stark et al., Annu. Rev. Biochem., 1998, 67, 227-264 and Samuel, Clin. Micro. Rev., 2001, 14, 778-809 ).
- siRNAs mediate potent knock-down in a variety of mammalian cell lines and probably escaped the adverse non-specific effects of long dsRNA in mammalian cells.
- This discovery was a hallmark in modern biology and the application of siRNAs as therapeutics soon became an attractive field of research (Reviewed by McManus and Sharp, Nature Reviews Genetics, 2002, 3, 737-747 and Thompson, DDT, 2002, 7, 912-917 ).
- RNA analogues are much more stable in biological media, and that the increased stability is also induced to the proximate native RNA residues. By greater stability is mainly meant increased nuclease resistance but also better cellular uptake and tissue distribution may be conferred by such modifications.
- Pre-siRNA ( Parrish et al. Mol. Cell, 2000, 6, 1077-1087 ) show tolerance for certain backbone modifications for RNAi in C. elegans.
- phosphorothioates are tolerated in both the sense and antisense strand and so are 2'-fluorouracil instead of uracil.
- 2'-aminouracil and 2'-aminocytidine reduce the RNAi activity when incorporated into the sense strand and the activity is completely abolished when incorporated in the antisense strand.
- UU 3' overhangs can be exchanged with 2'deoxythymidine 3' overhangs and are well tolerated ( Elbashir et al., Nature, 2001, 411, 494-498 and Boutla et al., Curr. Biol., 2001, 11, 1776-1780 ).
- DNA monomers can be incorporated in the sense strand without compromising the activity.
- Nyhimnen et al. (Cell, 2001, 107, 309-321 ) showed the need for ATP in making siRNA out of RNAi, but also in the later steps to exert the siRNA activity. ATP is needed for unwinding and maintaining a 5'-phosphate for RISC recognition. The 5'-phosphate is necessary for siRNA activity.
- Martinez et al. (Cell, 2002, 110, 563-574 ) showed that a single strand can reconstitute the RNA-induced silencing complex (RISC, Hammond et al., Nature, 2000, 404, 293-296 ) and that a single antisense strand has activity especially when 5'-phosphorylated. 5'-antisense strand modification inhibits activity while both the 3' end and the 5' end of the sense strand can be modified.
- Amarzguioui et al. confirmed the above-mentioned findings, and it was concluded that a mismatch is tolerated as long as it is not too close to the 5' end of the antisense strand.
- a mismatch 3-5 nucleotides from the 5' end of the antisense strand markedly diminishes the activity.
- two mismatches are tolerated if they are in the "middle" or towards the 3' end of the antisense strand, though with a slightly reduced activity.
- ENA bi-cyclic nucleoside analogue
- siRNA Hamada et al., Antisense and Nucl. Acid Drug Dev., 2002, 12, 301-309 . It was shown that two ENA thymidines in the 5' end of the sense strand deteriorated the effect. It was concluded by Hamada et al. (2002) that: " using 2'-O,4'-C-ethylene thymidine, which is a component of ethylene-bridged nucleic acids (ENA), completely abolished RNAi".
- the antisense strand is more sensitive to modifications than is the sense strand. Without being limited to any specific theory, this phenomena is, at least partly, believed to be based on the fact that the structure of the antisense/target duplex has to be native A-form RNA.
- the sense strand of siRNA can be regarded as a "vehicle" for the delivery of the antisense strand to the target and the sense strand is not participating in the enzyme-catalysed degradation of RNA.
- modifications in the sense strand is tolerated within a certain window even though the modifications induce changes to the A-form structure of the siRNA. If changes are introduced in the antisense strand they have to be structurally balanced within the recognition frame of the native RNA induced silencing complex (RISC).
- RISC native RNA induced silencing complex
- siRNAs have been shown to be able to potently suppress translation of complementary mRNAs inside cells.
- the mechanism by which these molecules work have been characterised in some detail. Briefly, after introduction into the cell by transfection one of the two RNA strands of the siRNA gets incorporated into the an enzyme complex (termed RISC), which thereby acquires the ability to bind to and cleave a mRNA containing a complementary sequence (thereby preventing its translation into protein). It has been shown that each of the two strands of the siRNA can be incorporated into the RISC complex, but that the strand that forms the weakest basepair at its 5'-end is preferred.
- RISC an enzyme complex
- any siRNA will - to a different extent - lead to the production of a mixture of activated RISC complexes that can cleave both the intended target as well as non-targets. It is evident that when siRNAs are used as a therapeutic drug it is highly desirable that the vast majority, preferably all, of the activated RISC complex contains the siRNA strand that is complementary to the desired target.
- modified siRNAs that i ) eliminates incorporation of the non-desired siRNA strand into the RISC complex, and/or ii ) disables the mRNA's destructive activity of inappropriately incorporated siRNA strands, would be highly desirable as such siRNAs would be expected to exert fewer side-effects than the corresponding non-modified siRNA drug.
- the present invention is based on the surprising finding that the mRNA-cleaving capability of an activated RISC complex can be suppressed by modifying nucleotides at specific positions in the sense strand.
- the present invention relates to a modified siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a modified RNA nucleotide in at least position 10, calculated from the 5'-end.
- the present invention relates to a modified RNA oligomer comprising 12-35 monomers, wherein said oligomer comprises a modified RNA nucleotide in at least position 10, calculated from the 5'-end.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a modified siRNA according to the invention and a pharmaceutically acceptable diluent, carrier or adjuvant.
- the present invention relates to a modified siRNA according to the invention for use as a medicament.
- the present invention relates to the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of cancer, an infectious disease or an inflammatory disease.
- the oligomers of the present invention may be used in a method for treating cancer, an infectious disease or an inflammatory disease, said method comprising administering a modified siRNA according to the invention or a pharmaceutical composition according to the invention to a patient in need thereof.
- RNA or “small interfering RNA” refers to double-stranded RNA molecules from about 12 to about 35 ribonucleotides in length that are named for their ability to specifically interfere with protein expression.
- modified siRNA means that at least one of the ribonucleotides in the siRNA molecule has been modified in its ribose unit, in its nitrogenous base, in its internucleoside linkage group, or combinations thereof.
- nucleotide means a 2-deoxyribose (DNA) monomer or a ribose (RNA) monomer which is bonded through its number one carbon to a nitrogenous base, such as adenine (A), cytosine (C), thymine (T), guanine (G) or uracil (U), and which is bonded through its number five carbon atom to an internucleoside linkage group (as defined below) or to a terminal group (as defined below).
- a nitrogenous base such as adenine (A), cytosine (C), thymine (T), guanine (G) or uracil (U)
- RNA nucleotide or “ribonucleotide” encompasses a RNA monomer comprising a ribose unit which is bonded through its number one carbon to a nitrogenous base selected from the group consisting of A, C, G and U, and which is bonded through its number five carbon atom to a phosphate group or to a terminal group.
- DNA nucleotide or "2-deoxyribonucleotide” encompasses a DNA monomer comprising a 2-deoxyribose unit which is bonded through its number one carbon to a nitrogenous base selected from the group consisting of A, C, T and G, and which is bonded through its number five carbon atom to a phosphate group or to a terminal group.
- modified RNA nucleotide or “modified ribonucleotide” means that the RNA nucleotide in question has been modified in its ribose unit, in its nitrogenous base, in its internucleoside linkage group, or combinations thereof. Accordingly, a “modified RNA nucleotide” may contain a sugar moiety which differs from ribose, such as a ribose monomer where the 2'-OH group has been modified.
- RNA nucleotide may contain a nitrogenous base which differs from A, C, G and U (a "non-RNA nucleobase”), such as T or Me C.
- a “modified RNA nucleotide” may contain an internucleoside linkage group which is different from phosphate (-O-P(O) 2 -O-), such as phosphorothioate (-O-P(O,S)-O-).
- DNA nucleobase covers the following nitrogenous bases: A, C, T and G.
- RNA nucleobase covers the following nitrogenous bases: A, C, U and G.
- non-RNA nucleobase encompasses nitrogenous bases which differ from A, C, G and U, such as purines (different from A and G) and pyrimidines (different from C and U).
- nucleobase covers DNA nucleobases, RNA-nucleobases and non-RNA nucleobases.
- sugar moiety which differs from ribose refers to a pentose with a chemical structure that is different from ribose.
- sugar moieties which are different from ribose include ribose monomers where the 2'-OH group has been modified.
- locked nucleic acid monomer When used in the present context, the terms "locked nucleic acid monomer”, “locked nucleic acid residue”, “LNA monomer” or “LNA residue” refer to a bicyclic nucleotide analogue.
- LNA monomers are described in inter alia WO 99/14226 , WO 00/56746 , WO 00/56748 , WO 01/25248 , WO 02/28875 , WO 03/006475 and WO 03/095467 .
- the LNA monomer may also be defined with respect to its chemical formula.
- a “LNA monomer” as used herein has the chemical structure shown in Scheme 1 below: wherein X is selected from the group consisting of O, S and NR H , where R H is H or alkyl, such as C 1-4 -alkyl; Y is (-CH 2 ) r , where r is an integer of 1-4; Z and Z* are independently absent or selected from the group consisting of an internucleoside linkage group, a terminal group and a protection group; and B is a nucleobase.
- nucleoside linkage group is intended to mean a group capable of covalently coupling together two nucleosides, two LNA monomers, a nucleoside and a LNA monomer, etc.
- Specific and preferred examples include phosphate groups and phosphorothioate groups.
- nucleic acid is defined as a molecule formed by covalent linkage of two or more nucleotides.
- nucleic acid and polynucleotide are used interchangeable herein.
- a “nucleic acid” or a “polynucleotide” typically contains more than 35 nucleotides.
- oligonucleotide refers, in the context of the present invention, to an oligomer (also called oligo) of RNA, DNA and/or LNA monomers as well as variants and analogues thereof.
- an "oligonucleotide” typically contains 2-35 nucleotides, in particular 12-35 nucleotides.
- At least one encompasses an integer larger than or equal to 1, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and so forth.
- a and “an” as used about a nucleotide, an active agent, a LNA monomer, etc. is intended to mean one or more.
- the expression “a component (such as a nucleotide, an active agent, a LNA monomer or the like) selected from the group consisting of " is intended to mean that one or more of the cited components may be selected.
- expressions like “a component selected from the group consisting of A, B and C” is intended to include all combinations of A, B and C, i.e. A, B, C, A+B, A+C, B+C and A+B+C.
- thio-LNA refers to a locked nucleotide in which X in Scheme 1 is S.
- Thio-LNA can be in both the beta-D form and in the alpha-L form. Generally, the beta-D form of thio-LNA is preferred.
- the beta-D form of thio-LNA is shown in Scheme 2 as compound 2C.
- amino-LNA refers to a locked nucleotide in which X in Scheme 1 is NH or NR H , where R H is hydrogen or C 1-4 -alkyl. Amino-LNA can be in both the beta-D form and alpha-L form. Generally, the beta-D form of amino-LNA is preferred. The beta-D form of amino-LNA is shown in Scheme 2 as compound 2D.
- oxy-LNA refers to a locked nucleotide in which X in Scheme 1 is O. Oxy-LNA can be in both the beta-D form and alpha-L form. The beta-D form of oxy-LNA is preferred. The beta-D form and the alpha-L form are shown in Schemes 2 and 3 as compounds 2A and 2B, respectively.
- mRNA means the mRNA transcript(s) of a targeted gene, and any further transcripts, which may be identified.
- target nucleic acid encompass any RNA that would be subject to modulation, targeted cleavage, steric blockage (decrease the abundance of the target RNA and/or inhibit translation) guided by the antisense strand.
- the target RNA could, for example, be genomic RNA, genomic viral RNA, mRNA or a pre-mRNA
- target-specific nucleic acid modification means any modification to a target nucleic acid.
- the term "gene” means the gene including exons, introns, non-coding 5' and 3' regions and regulatory elements and all currently known variants thereof and any further variants, which may be elucidated.
- modulation means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene.
- inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.
- targeting an siLNA or siRNA compound to a particular target nucleic acid means providing the siRNA or siLNA oligonucleotide to the cell, animal or human in such a way that the siLNA or siRNA compounds are able to bind to and modulate the function of the target.
- hybridisation means hydrogen bonding, which may be Watson-Crick, Hoogsteen, reversed Hoogsteen hydrogen bonding, etc., between complementary nucleoside or nucleotide bases.
- the four nucleobases commonly found in DNA are G, A, T and C of which G pairs with C, and A pairs with T.
- RNA T is replaced with uracil (U), which then pairs with A.
- the chemical groups in the nucleobases that participate in standard duplex formation constitute the Watson-Crick face.
- Hoogsteen showed a couple of years later that the purine nucleobases (G and A) in addition to their Watson-Crick face have a Hoogsteen face that can be recognised from the outside of a duplex, and used to bind pyrimidine oligonucleotides via hydrogen bonding, thereby forming a triple helix structure.
- complementary refers to the capacity for precise pairing between two nucleotides sequences with one another. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the corresponding position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position.
- the DNA or RNA strand are considered complementary to each other when a sufficient number of nucleotides in the oligonucleotide can form hydrogen bonds with corresponding nucleotides in the target DNA or RNA to enable the formation of a stable complex.
- siLNA or siRNA compound need not be 100% complementary to its target nucleic acid.
- complementary and specifically hybridisable thus imply that the siLNA or siRNA compound binds sufficiently strong and specific to the target molecule to provide the desired interference with the normal function of the target whilst leaving the function of non-target mRNAs unaffected
- conjugate is intended to indicate a heterogenous molecule formed by the covalent attachment of a compound as described herein to one or more non-nucleotide or non-polynucleotide moieties.
- non-nucleotide or non-polynucleotide moieties include macromolecular agents such as proteins, fatty acid chains, sugar residues, glycoproteins, polymers, or combinations thereof.
- proteins may be antibodies for a target protein.
- Typical polymers may be polyethylene glycol (PEG).
- C 1-6 -alkyl is intended to mean a linear or branched saturated hydrocarbon chain wherein the longest chains has from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.
- a branched hydrocarbon chain is intended to mean a C 1-6 -alkyl substituted at any carbon with a hydrocarbon chain.
- C 1-4 -alkyl is intended to mean a linear or branched saturated hydrocarbon chain wherein the longest chains has from one to four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
- a branched hydrocarbon chain is intended to mean a C 1-4 -alkyl substituted at any carbon with a hydrocarbon chain.
- C 1-6 -alkoxy is intended to mean C 1-6 -alkyl-oxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy and hexoxy.
- C 2-6 -alkenyl is intended to mean a linear or branched hydrocarbon group having from two to six carbon atoms and containing one or more double bonds.
- Illustrative examples of C 2-6 -alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
- the position of the unsaturation may be at any position along the carbon chain.
- C 2-6 -alkynyl is intended to mean linear or branched hydrocarbon groups containing from two to six carbon atoms and containing one or more triple bonds.
- Illustrative examples of C 2-6 -alkynyl groups include acetylene, propynyl, butynyl, pentynyl and hexynyl.
- the position of unsaturation may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C 2-6 -alkynyl” is a di-yne or enedi-yne as is known to the person skilled in the art.
- epithelial tissue covers or lines the body surfaces inside and outside the body. Examples of epithelial tissue are the skin and the mucosa and serosa that line the body cavities and internal organs, such as intestines, urinary bladder, uterus, etc. Epithelial tissue may also extend into deeper tissue layers to from glands, such as mucus-secreting glands.
- sarcoma is intended to indicate a malignant tumor growing from connective tissue, such as cartilage, fat, muscles, tendons and bones.
- glioma when used herein, is intended to cover a malignant tumor originating from glial cells.
- LNA monomers can be used freely in the design of modified siLNAs at both 3'-overhangs and at the 5'-end of the sense strand with full activation of the siLNA effect and down-regulation of protein production
- the present inventors have surprisingly found that the mRNA-cleaving capability of an activated RISC complex can be suppressed by modifying the sense strand of a siRNA in certain specific positions.
- the helicase can thereby be directed to unwinding from the other 5'-end (antisense strand 5'-end). In this way the incorporation of the antisense/guiding strand into RISC can be controlled.
- the helicase starts unwinding the siRNA duplex at the weakest binding end. The released 3'-end is probably targeted for degradation while the remaining strand is incorporated in the RISC.
- Efficient siRNAs show accumulation of the antisense/guiding strand and weaker base pairing in the 5'-end of the antisense/guiding strand. Unwanted side effects may possibly be avoided by having only the correct strand (the antisense/guiding strand) in RISC and not the unwanted sense strand (not complementary to the desired target RNA). This mechanism is illustrated in Fig. 1 .
- modification of the position 12 backbone i.e. the sugar moiety and/or the Internucleoside linkage group
- the present invention relates to a modified siRNA which comprises a sense strand and an antisense strand, wherein the sense strand comprises a modified RNA nucleotide in at least positions 10 and optionally at least one position selected from the group consisting of position 11, and position 12, calculated from the 5'-end.
- the RNA nucleotide is modified in its base structure, i.e. the modified RNA nucleotide comprises a non-RNA nucleobase.
- the sense strand comprises a non-RNA nucleobase in at least one position selected from the group consisting of position 9, position 10, position 11, position 12 and position 13, calculated from the 5'-end. More preferably, the sense strand comprises a non-RNA nucleobase in a position selected from the group consisting of position 10, position 11 and both of positions 10 and 11, calculated from the 5'-end. Most preferably, the sense strand comprises a non-RNA nucleobase in position 10, calculated from the 5'-end.
- the non-RNA nucleobase may be any purine or pyrimidine which is different from adenine (A), cytosine (C), uracil (U) and guanine (G).
- specific examples of such non-RNA nucleobases include thymine (T), 5-methylcytosine ( Me C), isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 5-propyny-6-fluoroluracil, 5-methylthiazoleuracil, 6-aminopurine, 2-aminopurine, inosine, 2,6-diaminopurine, 7-propyne-7-deazaadenine, 7-propyne-7-deazaguanine and 2-chloro-6-aminopurine, in particular T or Me C.
- the actual selection of the non-RNA nucleobase will depend on the corresponding (or matching) nucleotide present in the antisense strand.
- the corresponding antisense nucleotide is A it will normally be necessary to select a non-RNA nucleotide which is capable of establishing hydrogen bonds to A.
- a typical example of a preferred non-RNA nucleobase is T.
- a typical example of a preferred non-RNA nucleobase is Me C.
- the RNA nucleotide is modified in its sugar moiety, i.e. the modified RNA nucleotide comprises a sugar moiety which differs from ribose.
- the sense strand comprises a sugar moiety which differs from ribose, in at least one position selected from the group consisting of position 9, position 10, position 11, position 12 and position 13, calculated from the 5'-end. More preferably, the sense strand comprises a sugar moiety which differs from ribose, in at least one position selected from the group consisting of position 11, position 12 and position 13, calculated from the 5'-end. Most preferably, the sense strand comprises a sugar moiety which differs from ribose in position 12, calculated from the 5'-end.
- the sugar moiety which differs from ribose is modified in its 2'-OH group.
- the ribose 2'-OH group has been substituted with a group selected from the group consisting of -H, -O-CH 3 , -O-CH 2 -CH 2 -O-CH 3 , -O-CH 2 -CH 2 -CH 2 -NH 2 , -O-CH 2 -CH 2 -CH 2 -OH and -F, in particular -H.
- the sugar moiety which differs from ribose is LNA.
- the LNA may be selected from the group consisting of thio-LNA, amino-LNA, oxy-LNA and ena-LNA. These LNAs have the general chemical structure shown in Scheme 1 below: wherein X is selected from the group consisting of O, S and NR H , where R H is H or alkyl, such as C 1-4 -alkyl; Y is (-CH 2 ) r , where r is an integer of 1-4 Z and Z* are independently absent or selected from the group consisting of an internucleoside linkage group, a terminal group and a protection group; and B is a nucleobase.
- X is selected from the group consisting of O, S and NR H , where R H is H or alkyl, such as C 1-4 -alkyl
- Y is (-CH 2 ) r , where r is an integer of 1-4 Z and Z* are independently absent or selected from the group consisting of an internucleoside linkage group, a terminal
- r is 1, i.e. a preferred LNA monomer has the chemical structure shown in Scheme 2 below: wherein Z, Z*, R H and B are defined above.
- X is O and r is 1, i.e. an even more preferred LNA monomer has the chemical structure shown in Scheme 3 below: wherein Z, Z* and B are defined above.
- the LNA monomer is the beta-D form, i.e. the LNA monomer has the chemical structure indicated in 2A above.
- Z and Z* which serve for an internucleoside linkage, are independently absent or selected from the group consisting of an internucleoside linkage group, a terminal group and a protection group depending on the actual position of the LNA monomer within the compound. It will be understood that in embodiments where the LNA monomer is located at the 3' end, Z is a terminal group and Z* is an internucleoside linkage. In embodiments where the LNA monomer is located at the 5' end, Z is absent and Z* is a terminal group. In embodiments where the LNA monomer is located within the nucleotide sequence, Z is absent and Z* is an internucleoside linkage group.
- internucleoside linkage groups include -O-P(O) 2 -O-, -O-P(O,S)-O-,-O-P(S) 2 -O-, -S-P(O) 2 -O-, -S-P(O,S)-O-, -S-P(O) 2 -O-, -O-P(O) 2 -S-, -O-P(O,S)-S-, -S-P(O) 2 -S-, -O-PO(R H )-O-, O-PO(OCH 3 )-O-, -O-PO(NR H )-O-, -O-PO(OCH 2 CH 2 S-R)-O-, -O-PO(BH 3 )-O-, -O-PO(NHR H )-O-, -O-P(O) 2 -NR H -, -NR H -P(O) 2 -NR H
- the internucleoside linkage group is a phosphate group (-O-P(O) 2 -O-), a phosphorothioate group (-O-P(O,S)-O-) or the compound may contain both phosphate groups and phosphorothioate groups.
- terminal groups include terminal groups selected from the group consisting of hydrogen, azido, halogen, cyano, nitro, hydroxy, Prot-O-, Act-O-, mercapto, Prot-S-, Act-S-, C 1-6 -alkylthio, amino, Prot-N(R H )-, Act-N(R H )-, mono- or di(C 1-6 -alkyl)amino, optionally substituted C 1-6 -alkoxy, optionally substituted C 1-6 -alk optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkenyloxy, optionally substituted C 2-6 -alkynyl, optionally substituted C 2-6 -alkynyloxy, monophosphate including protected monophosphate, monothiophosphate including protected monothiophosphate, diphosphate including protected diphosphate, dithiophosphate including protected dithiophosphate, triphosphate including protected triphosphate, trithiophosphat
- phosphate protection groups include S-acetylthioethyl (SATE) and S-pivaloylthioethyl (t-butyl-SATE).
- terminal groups include DNA intercalators, photochemically active groups, thermochemically active groups, chelating groups, reporter groups, ligands, carboxy, sulphono, hydroxymethyl, Prot-O-CH 2 -, Act-O-CH 2 -, aminomethyl, Prot-N(R H )-CH 2 -, Act-N(R H )-CH 2 -, carboxymethyl, sulphonomethyl, where Prot is a protection group for -OH, -SH and -NH(R H ), and Act is an activation group for -OH, -SH, and -NH(R H ), and R H is hydrogen or C 1-6 -alkyl.
- protection groups for -OH and -SH groups include substituted trityl, such as 4,4'-dimethoxytrityloxy (DMT), 4-monomethoxytrityloxy (MMT); trityloxy, optionally substituted 9-(9-phenyl)xanthenyloxy (pixyl), optionally substituted methoxytetrahydro-pyranyloxy (mthp); silyloxy, such as trimethylsilyloxy (TMS), triisopropylsilyloxy (TIPS), tert -butyldimethylsilyloxy (TBDMS), triethylsilyloxy, phenyldimethylsilyloxy; tert- butylethers; acetals (including two hydroxy groups); acyloxy, such as acetyl or halogen-substituted acetyls, e.g .
- DMT 4,4'-dimethoxytrityloxy
- amine protection groups include fluorenylmethoxycarbonylamino (Fmoc), tert- butyloxycarbonylamino (BOC), trifluoroacetylamino, allyloxycarbonylamino (alloc, AOC), Z-benzyloxycarbonylamino (Cbz), substituted benzyloxycarbonylamino, such as 2-chloro benzyloxycarbonylamino (2-ClZ), monomethoxytritylamino (MMT), dimethoxytritylamino (DMT), phthaloylamino, and 9-(9-phenyl)xanthenylamino (pixyl).
- Fmoc fluorenylmethoxycarbonylamino
- BOC tert- butyloxycarbonylamino
- trifluoroacetylamino allyloxycarbonylamino (alloc, AOC)
- the activation group preferably mediates couplings to other residues and/or nucleotide monomers and after the coupling has been completed the activation group is typically converted to an internucleoside linkage.
- activation groups include optionally substituted O-phosphoramidite, optionally substituted O-phosphortriester, optionally substituted O-phosphordiester, optionally substituted H-phosphonate, and optionally substituted O-phosphonate.
- phosphoramidite means a group of the formula -P(OR x )-N(R y ) 2 , wherein R x designates an optionally substituted alkyl group, e.g.
- R y designates optionally substituted alkyl groups, e.g . ethyl or isopropyl, or the group -N(R y ) 2 forms a morpholino group (-N(CH 2 CH 2 ) 2 O).
- R x preferably designates 2-cyanoethyl and the two R y are preferably identical and designates isopropyl. Accordingly, a particularly preferred phosphoramidite is N,N-diisopropyl- O -(2-cyanoethyl)phosphoramidite.
- B is a nucleobase which may be of natural or non-natural origin.
- nucleobases include adenine (A), cytosine (C), 5-methylcytosine ( Me C), isocytosine, pseudoisocytosine, guanine (G), thymine (T), uracil (U), 5-bromouracil, 5-propynyluracil, 5-propyny-6, 5-methylthiazoleuracil, 6-aminopurine, 2-aminopurine, inosine, 2,6-diaminopurine, 7-propyne-7-deazaadenine, 7-propyne-7-deazaguanine and 2-chloro-6-aminopurine.
- the RNA nucleotide is modified in its internucleoside linkage group structure, i.e. the modified RNA nucleotide comprises an internucleoside linkage group which differs from phosphate.
- the sense strand comprises an internucleoside linkage group which differs from phosphate, in at least one position selected from the group consisting of position 9, position 10, position 11, position 12 and position 13, calculated from the 5'-end. More preferably, the sense strand comprises an internucleoside linkage group which differs from phosphate, in at least one position selected from the group consisting of position 11, position 12 and position 13, calculated from the 5'-end. Most preferably, the sense strand comprises an internucleoside linkage group which differs from phosphate in position 12, calculated from the 5'-end.
- the sense strand comprises an internucleoside linkage group which differs from phosphate in position X, calculated from the 5'-end
- the internucleoside linkage group establishes a linkage between the 3'-position of the residue in position X and the 5'-position of the residue in position X+1, calculated from the 5'-end.
- internucleoside linkage groups which differ from phosphate (-O-P(O) 2 -O-) include -O-P(O,S)-O-, -O-P(S) 2 -O-, -S-P(O) 2 -O-, -S-P(O,S)-O-, -S-P(O) 2 -O-, -O-P(O) 2 -S-, -O-P(O,S)-S-, -S-P(O) 2 -S-, -O-PO(R H )-O-, O-PO(OCH 3 )-O-, -O-PO(NR H )-O-,-O-PO(OCH 2 CH 2 S-R)-O-, -O-PO(BH 3 )-O-, -O-PO(NHR H )-O-, -O-P(O) 2 -NR H -, -NR H -P-
- any of the above-mentioned modifications may be combined and/or the modified siRNA may contain other modifications which serve the purpose of increasing the biostability (corresponding to an increased T m ), increasing the nuclease resistance, improving the cellular uptake and/or improving the tissue distribution.
- At least one of the strands of the modified siRNA further comprises at least one modified RNA nucleotide.
- This further modification may be a modification selected from the group consisting of a non-RNA nucleobase, a sugar moiety which differs from ribose, an internucleoside linkage group which differs from phosphate, and combinations thereof.
- the sense strand comprises at least one LNA monomer, such as 1-10 LNA monomers, e.g. 1-5 or 1-3 LNA monomers.
- the antisense strand comprises at least one LNA monomer, such as 1-10 LNA monomers, e.g. 1-5 or 1-3 LNA monomers.
- the sense strand comprises at least one LNA monomer and the antisense strand comprises at least one LNA monomer.
- the sense strand typically comprises 1-10 LNA monomers, such as 1-5 or 1-3 LNA monomers
- the antisense strand typically comprises 1-10 LNA monomers, such as 1-5 or 1-3 LNA monomers.
- the sense strand comprises a sugar moiety which differs from ribose in position 12, calculated from the 5'-end, and a non-RNA nucleobase in position 10, calculated from the 5'-end.
- LNA monomers incorporated into oligos will induce a RNA-like structure of the oligo and the hybrid that it may form. It has also been shown that LNA residues modify the structure of DNA residues, in particular when the LNA residues is incorporated in the proximity of 3'-end. LNA monomer incorporation towards the 5'-end seems to have a smaller effect. This means that it is possible to modify RNA strands which contain DNA monomers, and if one or more LNA residues flank the DNA monomers they too will attain a RNA-like structure. Therefore, DNA and LNA monomers can replace RNA monomers and still the oligo will attain an overall RNA-like structure. As DNA monomers are considerably cheaper than RNA monomers, easier to synthesise and more stable towards nucleolytic degradation, such modifications will therefore improve the overall use and applicability of siRNAs.
- At least one (such as one) LNA monomer is located at the 5'-end of the sense strand.
- at least two (such as two) LNA monomers are located at the 5'-end of the sense strand.
- the sense strand comprises at least one (such as one) LNA monomer located at the 3'-end of the sense strand. More preferably, at least two (such as two) LNA monomers are located at the 3'-end of the of the sense strand.
- the sense strand comprises at least one (such as one) LNA monomer located at the 5'-end of the sense strand and at least one (such as one) LNA monomer located at the 3'-end of the sense strand. Even more preferably, the sense strand comprises at least two (such as two) LNA monomers located at the 5'-end of the sense strand and at least two (such as two) LNA monomers located at the 3'-of the sense strand.
- At least one (such as one) LNA monomer is located at the 3'-end of the antisense strand. More preferably, at least two (such as two) LNA monomers are located at the 3'-end of the antisense strand. Even more preferably, at least three (such as three) LNA monomers are located at the 3'-end of the antisense strand. In a particular preferred embodiment of the invention, no LNA monomer is located at or near (i.e. within 1, 2, or 3 nucleotides) the 5'-end of the antisense strand.
- the sense strand comprises at least one LNA monomer at the 5'-end and at least one LNA monomer at the 3'-end
- the antisense strand comprises at least one LNA monomer at the 3'-end. More preferably, the sense strand comprises at least one LNA monomer at the 5'-end and at least one LNA monomer at the 3'-end, and the antisense strand comprises at least two LNA monomers at the 3'-end. Even more preferably, the sense strand comprises at least two LNA monomers at the 5'-end and at least two LNA monomers at the 3'-end, and the antisense strand comprises at least two LNA monomers at the 3'-end.
- the sense strand comprises at least two LNA monomers at the 5'-end and at least two LNA monomers at the 3'-end
- the antisense strand comprises at least three LNA monomers at the 3'-end. It will be understood that in the most preferred embodiment, none of the above-mentioned compounds contain a LNA monomer which is located at the 5'-end of the antisense strand.
- the LNA monomer is located close to the 3'-end, i.e. at postion 2, 3 or 4, preferably at position 2 or 3, in particular at position 2, calculated from the 3'-end.
- the sense strand comprises a LNA monomer located at position 2, calculated from the 3'-end.
- the sense strand comprises LNA monomers located at position 2 and 3, calculated from the 3'-end.
- the sense strand comprises at least one (such as one) LNA monomer located at the 5'-end and a LNA monomer located at position 2 (calculated from the 3'-end). In a further embodiment, the sense strand comprises at least two (such as two) LNA monomers located at the 5'-end of the sense strand a LNA monomer located at positions 2 (calculated from the 3' end).
- the antisense strand comprises a LNA monomer at position 2, calculated from the 3'-end. More preferably, the antisense strand comprises LNA monomers in position 2 and 3, calculated from the 3'-end. Even more preferably, the antisense strand comprises LNA monomers located at position 2, 3 and 4, calculated from the 3'-end. In a particular preferred embodiment of the invention, no LNA monomer is located at or near (i.e. within 1, 2, or 3 nucleotides) the 5'-end of the antisense strand.
- the sense strand comprises at least one LNA monomer at the 5'-end and a LNA monomer at position 2 (calculated from the 3' end), and the antisense strand comprises a LNA monomer located at position 2 (calculated from the 3'-end). More preferably, the sense strand comprises at least one LNA monomer at the 5'-end and a LNA monomer at position 2 (calculated from the 3'-end), and the antisense strand comprises LNA monomers at position 2 and 3 (calculated from the 3'-end).
- the sense strand comprises at least two LNA monomers at the 5'-end and LNA monomers at position 2 and 3 (calculated from the 3'-end), and the antisense strand comprises LNA monomers at position 2 and 3 (calculated from the 3'-end). Still more preferably, the sense strand comprises at least two LNA monomers at the 5'-end and LNA monomers at position 2 and 3 (calculated from the 3'-end), and the antisense strand comprises LNA monomers at position 2, 3 and 4 (calculated from the 3'-end). It will be understood that in the most preferred embodiment, none of the above-mentioned compounds contain a LNA monomer which is located at the 5'-end of the antisense strand.
- each strand typically comprises 12-35 monomers. It will be understood that these numbers refer to the total number of naturally occurring and modified nucleotides. Thus, the total number of naturally occurring and modified nucleotides will typically not be lower than 12 and will typically not exceed 35. In an interesting embodiment of the invention, each strand comprises 17-25 monomers, such as 20-22 or 20-21 monomers.
- the modified siRNA according to the invention may be blunt ended or may contain overhangs.
- at least one of the strands comprises a 3'-overhang.
- the sense and antisense strand both comprise a 3'-overhang.
- only the sense strand comprises a 3'-overhang.
- the 3'-overhang is 1-7 monomers in length, preferably 1-5 monomers in length, such as 1-3 monomers in length, e.g. 1 monomer in length, 2 monomers in length or 3 monomers in length.
- the strands may have a 5'-overhang.
- the 5'-overhang will be of 1-7 monomers in length, preferably 1-3, such as 1, 2 or 3, monomers in length.
- the sense strand may contain a 5'-overhang
- the antisense strand may contain a 5'-overhang
- both of the sense and antisense strands may contain 5'-overhangs.
- the sense strand may contain both a 3'- and a 5'-overhang.
- the antisense strand may contain both a 3'- and a 5'-overhang.
- the LNA monomers are useful for the purposes of the present invention.
- the LNA monomer is in the beta-D form, corresponding to the LNA monomers shown as compounds 2A, 2C and 2D.
- the currently most preferred LNA monomer is the monomer shown as compound 2A in Schemes 2 and 3 above, i.e. the currently most preferred LNA monomer is the beta-D form of oxy-LNA.
- the modified siRNA of the invention is linked to one or more ligands so as to form a conjugate.
- the ligand(s) serve(s) the role of increasing the cellular uptake of the conjugate relative to the non-conjugated compound.
- This conjugation can take place at the terminal 5'-OH and/or 3'-OH positions, but the conjugation may also take place at the sugars and/or the nucleobases.
- the growth factor to which the antisense oligonucleotide may be conjugated may comprise transferrin or folate.
- Transferrin-polylysine-oligonucleotide complexes or folate-polylysine-oligonucleotide complexes may be prepared for uptake by cells expressing high levels of transferrin or folate receptor.
- conjugates/lingands are cholesterol moieties, duplex intercalators such as acridine, poly-L-lysine, "end-capping" with one or more nuclease-resistant linkage groups such as phosphoromonothioate, and the like.
- the compounds or conjugates of the invention may also be conjugated or further conjugated to active drug substances, for example, aspirin, ibuprofen, a sulfa drug, an antidiabetic, an antibacterial agent, a chemotherapeutic agent or an antibiotic.
- active drug substances for example, aspirin, ibuprofen, a sulfa drug, an antidiabetic, an antibacterial agent, a chemotherapeutic agent or an antibiotic.
- the modified siRNAs of the invention may be produced using the polymerisation techniques of nucleic acid chemistry, which is well known to a person of ordinary skill in the art of organic chemistry.
- nucleic acid chemistry which is well known to a person of ordinary skill in the art of organic chemistry.
- standard oligomerisation cycles of the phosphoramidite approach S. L. Beaucage and R. P. Iyer, Tetrahedron, 1993, 49, 6123 ; and S. L. Beaucage and R. P. Iyer, Tetrahedron, 1992, 48, 2223
- other chemistries such as the H-phosphonate chemistry or the phosphortriester chemistry may also be used.
- Purification of the individual strands may be done using disposable reversed phase purification cartridges and/or reversed phase HPLC and/or precipitation from ethanol or butanol.
- Gel electrophoresis, reversed phase HPLC, MALDI-MS, and ESI-MS may be used to verify the purity of the synthesised LNA-containing oligonucleotides.
- solid support materials having immobilised thereto a nucleobase-protected and 5'-OH protected LNA are especially interesting for synthesis of the LNA-containing oligonucleotides where a LNA monomer is included at the 3' end.
- the solid support material is preferable CPG or polystyrene onto which a 3'-functionalised, optionally nucleobase protected and optionally 5'-OH protected LNA monomer is linked.
- the LNA monomer may be attached to the solid support using the conditions stated by the supplier for that particular solid support material.
- the modified siRNAs of the invention will constitute suitable drugs with improved properties.
- the design of a potent and safe RNAi drug requires the fine-tuning of various parameters such as affinity/specificity, stability in biological fluids, cellular uptake, mode of action, pharmacokinetic properties and toxicity.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a modified siRNA according to the invention and a pharmaceutically acceptable diluent, carrier or adjuvant.
- the present invention relates to a modified siRNA according to the invention for use as a medicament.
- dosing is dependent on severity and responsiveness of the disease state to be treated, and the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved.
- Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient.
- Optimum dosages may vary depending on the relative potency of individual siLNAs. Generally it can be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ⁇ g to 1 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 10 years or by continuous infusion for hours up to several months. The repetition rates for dosing can be estimated based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state.
- the invention also relates to a pharmaceutical composition, which comprises at least one modified siRNA of the invention as an active ingredient.
- the pharmaceutical composition according to the invention optionally comprises a pharmaceutical carrier, and that the pharmaceutical composition optionally comprises further compounds, such as chemotherapeutic compounds, anti-inflammatory compounds, antiviral compounds and/or immuno-modulating compounds.
- modified siRNAs of the invention can be used "as is” or in form of a variety of pharmaceutically acceptable salts.
- pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the herein-identified modified siRNAs and exhibit minimal undesired toxicological effects.
- Non-limiting examples of such salts can be formed with organic amino acid and base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N -dibenzylethylene-diamine, D -glucosamine, tetraethylammonium, or ethylenediamine.
- metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N -dibenzylethylene-diamine, D -glucosamine, tetraethylammonium, or ethylenediamine.
- the modified siRNA may be in the form of a pro-drug.
- Oligonucleotides are by virtue negatively charged ions. Due to the lipophilic nature of cell membranes the cellular uptake of oligonucleotides are reduced compared to neutral or lipophilic equivalents. This polarity "hindrance” can be avoided by using the pro-drug approach (see e.g. Crooke, R. M. (1998) in Crooke, S. T. Antisense research and Application. Springer-Verlag, Berlin, Germany, vol. 131, pp. 103-140 ). In this approach the oligonucleotides are prepared in a protected manner so that the oligo is neutral when it is administered.
- protection groups are designed in such a way that they can be removed when the oligo is taken up by the cells.
- examples of such protection groups are S-acetylthioethyl (SATE) or S-pivaloylthioethyl ( t -butyl-SATE). These protection groups are nuclease resistant and are selectively removed intracellulary.
- Pharmaceutically acceptable binding agents and adjuvants may comprise part of the formulated drug.
- Capsules, tablets and pills etc. may contain for example the following compounds: microcrystalline cellulose, gum or gelatin as binders; starch or lactose as excipients; stearates as lubricants; various sweetening or flavouring agents.
- the dosage unit may contain a liquid carrier like fatty oils.
- coatings of sugar or enteric agents may be part of the dosage unit.
- the oligonucleotide formulations may also be emulsions of the active pharmaceutical ingredients and a lipid forming a micellular emulsion.
- a compound of the invention may be mixed with any material that do not impair the desired action, or with material that supplement the desired action.
- the formulation may include a sterile diluent, buffers, regulators of tonicity and antibacterials.
- the active compound may be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties.
- the preferred carriers are physiological saline or phosphate buffered saline.
- an oligomeric compound is included in a unit formulation such as in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious side effects in the treated patient.
- compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be (a) oral (b) pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, (c) topical including epidermal, transdermal, ophthalmic and to mucous membranes including vaginal and rectal delivery; or (d) parenteral including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
- pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer
- intratracheal intranasal
- topical including epidermal, transdermal, ophthalmic and to mucous membranes including vaginal and rectal delivery
- the pharmaceutical composition is administered IV, IP, orally, topically or as a bolus injection or administered directly in to the target organ.
- Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, sprays, suppositories, liquids and powders.
- Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
- Coated condoms, gloves and the like may also be useful.
- Preferred topical formulations include those in which the compounds of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants.
- compositions and formulations for oral administration include but is not restricted to powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets.
- Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.
- compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self- emulsifying solids and self-emulsifying semisolids. Delivery of drug to tumour tissue may be enhanced by carrier-mediated delivery including, but not limited to, cationic liposomes, cyclodextrins, porphyrin derivatives, branched chain dendrimers, polyethylenimine polymers, nanoparticles and microspheres ( Dass CR. J Pharm Pharmacol 2002; 54(1):3-27 ).
- compositions of the present invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- the compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels and suppositories.
- the compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
- Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
- the suspension may also contain stabilizers.
- the compounds of the invention may also be conjugated to active drug substances, for example, aspirin, ibuprofen, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.
- compositions of the invention may contain one or more siLNA compounds, targeted to a first nucleic acid and one or more additional siLNA compounds targeted to a second nucleic acid target. Two or more combined compounds may be used together or sequentially.
- therapeutic methods include administration of a therapeutically effective amount of a siLNA to a mammal, particularly a human.
- the present invention provides pharmaceutical compositions containing (a) one or more compounds of the invention, and (b) one or more chemotherapeutic agents.
- chemotherapeutic agents When used with the compounds of the invention, such chemotherapeutic agents may be used individually, sequentially, or in combination with one or more other such chemotherapeutic agents or in combination with radiotherapy. All chemotherapeutic agents known to a person skilled in the art are here incorporated as combination treatments with compound according to the invention.
- anti-inflammatory drugs including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, antiviral drugs, and immuno-modulating drugs may also be combined in compositions of the invention. Two or more combined compounds may be used together or sequentially.
- the present invention relates to the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of cancer.
- the modified siRNAs of the invention may be used in a method for treatment of, or prophylaxis against, cancer, said method comprising administering a modified siRNA of the invention or a pharmaceutical composition of the invention to a patient in need thereof.
- Such cancers may include lymphoreticular neoplasia, lymphoblastic leukemia, brain tumors, gastric tumors, plasmacytomas, multiple myeloma, leukemia, connective tissue tumors, lymphomas, and solid tumors.
- said cancer may suitably be in the form of a solid tumor.
- said cancer in the method for treating cancer disclosed herein said cancer may suitably be in the form of a solid tumor.
- said cancer is also suitably a carcinoma.
- the carcinoma is typically selected from the group consisting of malignant melanoma, basal cell carcinoma, ovarian carcinoma, breast carcinoma, non-small cell lung cancer, renal cell carcinoma, bladder carcinoma, recurrent superficial bladder cancer, stomach carcinoma, prostatic carcinoma, pancreatic carcinoma, lung carcinoma, cervical carcinoma, cervical dysplasia, laryngeal papillomatosis, colon carcinoma, colorectal carcinoma and carcinoid tumors. More typically, said carcinoma is selected from the group consisting of malignant melanoma, non-small cell lung cancer, breast carcinoma, colon carcinoma and renal cell carcinoma.
- the malignant melanoma is typically selected from the group consisting of superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral melagnoma, amelanotic melanoma and desmoplastic melanoma.
- the cancer may suitably be a sarcoma.
- the sarcoma is typically in the form selected from the group consisting of osteosarcoma, Ewing's sarcoma, chondrosarcoma, malignant fibrous histiocytoma, fibrosarcoma and Kaposi's sarcoma.
- the cancer may suitably be a glioma.
- a further embodiment is directed to the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of cancer, wherein said medicament further comprises a chemotherapeutic agent selected from the group consisting of adrenocorticosteroids, such as prednisone, dexamethasone or decadron; altretamine (hexalen, hexamethylmelamine (HMM)); amifostine (ethyol); aminoglutethimide (cytadren); amsacrine (M-AMSA); anastrozole (arimidex); androgens, such as testosterone; asparaginase (elspar); bacillus calmette-gurin; bicalutamide (casodex); bleomycin (blenoxane); busulfan (myleran); carboplatin (paraplatin); carmustine (BCNU, BiCNU); chlorambucil (leukeran); chlorodeoxyadenosine (2-CDA, cla
- the invention is further directed to the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of cancer, wherein said treatment further comprises the administration of a further chemotherapeutic agent selected from the group consisting of adrenocorticosteroids, such as prednisone, dexamethasone or decadron; altretamine (hexalen, hexamethylmelamine (HMM)); amifostine (ethyol); aminoglutethimide (cytadren); amsacrine (M-AMSA); anastrozole (arimidex); androgens, such as testosterone; asparaginase (elspar); bacillus calmette-gurin; bicalutamide (casodex); bleomycin (blenoxane); busulfan (myleran); carboplatin (paraplatin); carmustine (BCNU, BiCNU); chlorambucil (leukeran); chlorodeoxyadenosine (2
- the modified siRNA of the invention may be used in a method for treating cancer, said method comprising administering a modified siRNA of the invention or a pharmaceutical composition according to the invention to a patient in need thereof and further comprising the administration of a further chemotherapeutic agent.
- Said further administration may be such that the further chemotherapeutic agent is conjugated to the compound of the invention, is present in the pharmaceutical composition, or is administered in a separate formulation.
- the modified siLNA compounds according to the invention are used for targeting Severe Acute Respiratory Syndrome (SARS), which first appeared in China in November 2002.
- SARS Severe Acute Respiratory Syndrome
- WHO WHO over 8,000 people have been infected world-wide, resulting in over 900 deaths.
- a previously unknown coronavirus has been identified as the causative agent for the SARS epidemic ( Drosten C et al. N Engl J Med 2003,348,1967-76 ; and Fouchier RA et al. Nature 2003,423,240 ). Identification of the SARS-CoV was followed by rapid sequencing of the viral genome of multiple isolates ( Ruan et al. Lancet 2003,361,1779-85 ; Rota PA et al.
- the nucleotide sequence encoding the SARS-CoV RNA-dependent RNA polymerase (Pol) is highly conserved throughout the coronavirus family.
- the Pol gene product is translated from the genomic RNA as a part of a polyprotein, and uses the genomic RNA as a template to synthesize negative-stranded RNA and subsequently sub-genomic mRNA.
- the Pol protein is thus expressed early in the viral life cycle and is crucial to viral replication.
- the present invention relates the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of Severe Acute Respiratory Syndrome (SARS).
- the modified siRNAs of the invention may be used in a method for treating Severe Acute Respiratory Syndrome (SARS), said method comprising administering a modified siRNA according to the invention or a pharmaceutical composition according to the invention to a patient in need thereof.
- the compounds of the invention may be broadly applicable to a broad range of infectious diseases, such as diphtheria, tetanus, pertussis, polio, hepatitis B, hemophilus influenza, measles, mumps, and rubella.
- infectious diseases such as diphtheria, tetanus, pertussis, polio, hepatitis B, hemophilus influenza, measles, mumps, and rubella.
- the present invention relates the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of an infectious disease.
- the modified siRNAs of the invention may be used in a method for treating an infectious disease, said method comprising administering a modified siRNA according to the invention or a pharmaceutical composition according to the invention to a patient in need thereof.
- the inflammatory response is an essential mechanism of defense of the organism against the attack of infectious agents, and it is also implicated in the pathogenesis of many acute and chronic diseases, including autoimmune disorders.
- Inflammation is a complex process normally triggered by tissue injury that includes activation of a large array of enzymes, the increase in vascular permeability and extravasation of blood fluids, cell migration and release of chemical mediators, all aimed to both destroy and repair the injured tissue.
- the present invention relates to the use of a modified siRNA according to the invention for the manufacture of a medicament for the treatment of an inflammatory disease.
- the modified siRNAs of the invention may be used in a method for treating an inflammatory disease, said method comprising administering a modified siRNA according to the invention or a pharmaceutical composition according to the invention to a patient in need thereof.
- the inflammatory disease is a rheumatic disease and/or a connective tissue diseases, such as rheumatoid arthritis, systemic lupus erythematous (SLE) or Lupus, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, exfoliative psoriatic dermatitis, pemphigus vulgaris and Sjorgren's syndrome, in particular inflammatory bowel disease and Crohn's disease.
- SLE systemic lupus erythematous
- Lupus scleroderma
- polymyositis inflammatory bowel disease
- dermatomyositis ulcerative colitis
- Crohn's disease vasculitis
- psoriatic arthritis exfoliative psoriatic dermatitis
- pemphigus vulgaris and Sjorgren's syndrome
- the inflammatory disease may be a non-rheumatic inflammation, like bursitis, synovitis, capsulitis, tendinitis and/or other inflammatory lesions of traumatic and/or university origin.
- the modified siRNAs of the present invention can be utilized for as research reagents for diagnostics, therapeutics and prophylaxis.
- the modified siRNA may be used to specifically inhibit the synthesis of target genes in cells and experimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention.
- the siRNA oligonucleotides may be used to detect and quantitate target expression in cell and tissues by Northern blotting, in-situ hybridisation or similar techniques.
- an animal or a human, suspected of having a disease or disorder, which can be treated by modulating the expression of target is treated by administering the modified siRNA compounds in accordance with this invention.
- 5'-O-DMT (A(bz), C(bz), G(ibu) or T) linked to CPG were deprotected using a solution of 3% trichloroacetic acid (v/v) in dichloromethane. The CPG was washed with acetonitrile. Coupling of phosphoramidites (A(bz), G(ibu), 5-methyl-C(bz)) or T - ⁇ -cyanoethyl-phosphoramidite) was performed by using 0.08 M solution of the 5'-O-DMT-protected amidite in acetonitrile and activation was done by using DCI (4,5-dicyanoimidazole) in acetonitrile (0.25 M).
- the coupling reaction was carried out for 2 min. Thiolation was carried out by using Beaucage reagent (0.05 M in acetonitrile) and was allowed to react for 3 min. The support was thoroughly washed with acetonitrile and the subsequent capping was carried out by using standard solutions (CAP A) and (CAP B) to cap unreacted 5' hydroxyl groups. The capping step was then repeated and the cycle was concluded by acetonitrile washing.
- Beaucage reagent 0.05 M in acetonitrile
- 5'-O-DMT (A(bz), C(bz), G(ibu) or T) linked to CPG was deprotected by using the same procedure as described above. Coupling was performed by using 5'-O-DMT-A(bz), C(bz), G(ibu) or T- ⁇ -cyanoethylphosphoramidite (0.1 M in acetonitrile) and activation was done by DCI (0.25 M in acetonitrile). The coupling reaction was carried out for 7 minutes. Capping was done by using standard solutions (CAP A) and (CAP B) for 30 sec.
- the phosphite triester was oxidized to the more stable phosphate triester by using a standard solution of I 2 and pyridine in THF for 30 sec.
- the support was washed with acetonitrile and the capping step was repeated. The cycle was concluded by thorough acetonitrile wash.
- oligonucleotides were cleaved from the support and the ⁇ -cyanoethyl protecting group removed by treating the support with 35% NH 4 OH for 1 h at room temperature.
- the support was filtered off and the base protecting groups were removed by raising the temperature to 65°C for 4 hours. Ammonia was then removed by evaporation.
- oligos were either purified by reversed-phase-HPLC (RP-HPLC) or by anion exchange chromatography (AIE): RP-HPLC: Column: VYDAC TM , Cat. No. 218TP1010 (vydac) Flow rate: 3 ml/min Buffer: A (0.1 M ammonium acetate, pH 7.6) B (acetonitrile) Gradient: Time 0 10 18 22 23 28 B% 0 5 30 100 100 0 AIE: Column: Resource TM 15Q (amersham pharmacia biotech) Flow rate: 1.2 ml/min Buffer: A (0.1 M NaOH) B (0.1 M NaOH, 2.0 M NaCl) Gradient: Time 0 1 27 28 32 33 B% 0 25 55 100 100 0
- LNA/RNA oligonucleotides were synthesized DMT-off on a 1.0 ⁇ mole scale using an automated nucleic acid synthesiser (MOSS Expedite 8909) and using standard reagents. 1 H -tetrazole or 5-ethylthio-1 H -tetrazole were used as activators.
- the LNA A Bz , G lBu and T phosphoramidite concentration was 0.1 M in anhydrous acetonitrile.
- the Me C Bz was dissolved in 15 % THF in acetonitrile.
- the coupling time for all monomer couplings was 600 secs.
- RNA phosphoramidites (Glen Research, Sterling, Virginia) were N-acetyl and 2'-O-triisopropylsilyloxymethyl (TOM) protected.
- the monomer concentration was 0.1 M (anhydrous acetonitrile) and the coupling time was 900 secs.
- the oxidation time was set to be 50 sec.
- the solid support was DMT-LNA-CPG (1000 ⁇ , 30-40 ⁇ mole/g).
- Cleavage from the resin and nucleobase/phosphate deprotection was carried out in a sterile tube by treatment with 1.5 ml of a methylamine solution (1:1, 33% methylamine in ethanol:40% methylamine in water) at 35°C for 6 h or left overnight.
- the tube was centrifuged and the methylamine solution was transferred to second sterile tube.
- the methylamine solution was evaporated in a vacuum centrifuge.
- To remove the 2'-O-protection groups the residue was dissolved in 1.0 ml 1.0 M TBAF in THF and heated to 55°C for 15 min. and left at 35°C overnight.
- the THF was evaporated in a vacuum centrifuge leaving a light yellow gum, which was neutralised with approx.
- the gel was stained in CyberGold (Molecular Probes, 1:10000 in 0.9xTBE) for 30 min followed by scanning in a Bio-Rad FX Imager).
- the concentration of the oligonucleotide was measured by UV-spectrometry at 260 nm.
- Step Reagent Operation Volume Remarks 1 - Empty storage buffer - Discard 2 H 2 O (RNase-free) Wash 2 x full volume Discard 3 Oligo in buffer (RNase-free) Load 1.0 ml Discard 4 H 2 O (RNase-free) Elution 1.5 ml Collect - Contains oligo 5 H 2 O (RNase-free) "Elution" 0.5 ml Collect - Contains salt + small amount of oligo
- the cells used were the human embryonal kidney (HEK) 293 cell lines.
- HEK 293 cells were maintained in DMEM supplemented with 10% foetal bovine serum, penicillin, strepto-mycine and glutamine (Invitrogen, Paisely, UK).
- the plasmids used were pGL3-Control coding for firefly luciferace under the control of the SV40 promoter and enhancer and pRL-TK coding for Renilla luciferase under the control of HSV-TK promoter (Promega, Madison, WI, USA).
- transfection cells were seeded in 500 ⁇ l medium in 24-well plates in order to adhere and reach a confluency of 70 to 90% at the time of transfection.
- Cells were seeded in the medium without antibiotics and changed to 500 ⁇ l Opti-MEM I just before adding the transfection mix to the cells.
- a standard co-transfection mix was prepared for triplicate wells by separately adding 510 ng pGL3-Control, 51 ng pRL-TK and 340 ng siRNA to 150 ⁇ l Opti-MEM I (Invitrogen) and 3 ⁇ l LipofectAMINE 2000 (Invitrogen) to another 150 ⁇ l Opti-MEM I. The two solutions were mixed and incubated at room temperature for 20-30 minutes before adding to the cells.
- transfection mix 100 ⁇ l was added to each of the three wells. The final volume of medium plus transfection mix was 600 ⁇ l. The siLNA or siRNA concentration corresponded to about 13 nM. Cells were incubated with the transfection mix for 4 hours and the medium was then changed with fully supplemented DMEM.
- Cells were harvested in passive lysis buffer and assayed according to the protocol (Promega) using a NovoSTAR 96-well format luminometer with substrate dispenser (BMG Labtechnologies, Offenburg, Germany). 10 ⁇ l sample was applied in each well of a 96 well plate and 50 ⁇ l Luciferace Assay Reagent II (substrate for firefly luciferase) was added to a well by the luminometer and measured. Then, 50 ⁇ l Stop and Glow (stop solution for firefly luciferase and substrate for Renilla luciferase) was added and measured. The average of the luciferase activities measured for 10 sec. was used to calculate ratios between firefly and Renilla luciferase or the opposite.
- Luciferace Assay Reagent II substrate for firefly luciferase
- Stop and Glow stop solution for firefly luciferase and substrate for Renilla luciferase
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (15)
- Modifizierte siRNA, umfassend einen sense-Strang und einen antisense-Strang, wobei der sense-Strang in mindestens einer der Positionen 8-14, gezählt von dem 5'-Ende, ein modifiziertes RNA-Nukleotid umfasst und wobei der sense-Strang in Position 10, gezählt von dem 5'-Ende, eine Nicht-RNA-Nukleobase umfasst, wobei die Nicht-RNA-Nukleobase eine von Ribose verschiedene Zuckergruppe aufweist und wobei die modifizierte siRNA spezifisch die Proteinexpression stören kann.
- Modifizierte siRNA nach Anspruch 1, wobei der sense-Strang weiterhin eine Nicht-RNA-Nukleobase in Position 12, gezählt von dem 5'-Ende, umfasst.
- Modifizierte siRNA nach Anspruch 1, wobei der sense-Strang weiterhin eine Nicht-RNA-Nukleobase in Position 11, gezählt von dem 5'-Ende, umfasst.
- Modifizierte siRNA nach einem der Ansprüche 1-3, wobei die Nicht-RNA-Nukleobase ausgewählt ist aus der Gruppe, bestehend aus Thymin (T), 5-Methylcytosin (MeC), Isocytosin, Pseudoisocytosin, 5-Bromouracil, 5-Propinyluracil, 5-Propinyl-6-fluorouracil, 5-Methylthiazoluracil, 6-Aminopurin, 2-Aminopurin, Inosin, 2,6-Diaminopurin, 7-Propinyl-7-deazaadenin, 7-Propinyl-7-deazaguanin und 2-Chlor-6-aminopurin.
- Modifizierte siRNA nach Anspruch 4, wobei die Nicht-RNA-Nukleobase T oder MeC ist.
- Modifizierte siRNA nach Anspruch 5, wobei die Nicht-RNA-Nukleobase T ist.
- Modifizierte siRNA nach einem der Ansprüche 1-6, wobei sich die Zuckergruppe dadurch von Ribose unterscheidet, dass die 2'-OH-Gruppe von Ribose modifiziert ist.
- Modifizierte siRNA nach Anspruch 7, wobei die Zuckergruppe LNA ist.
- Modifizierte siRNA nach Anspruch 8, wobei die LNA ausgewählt ist aus der Gruppe, bestehend aus Thio-LNA, Amino-LNA, Oxy-LNA und Ena-LNA.
- Modifizierte siRNA nach Anspruch 9, wobei die LNA Oxy-LNA ist.
- Modifizierte siRNA nach Anspruch 10, wobei die Oxy-LNA in der Beta-D-Form vorliegt.
- Modifizierte siRNA nach einem der vorhergehenden Ansprüche, wobei der sense-Strang in Position 12, gezählt von dem 5'-Ende, eine von Ribose verschiedene Zuckergruppe umfasst und wobei der sense-Strang in Position 10, gezählt von dem 5'-Ende, eine Nicht-RNA-Nukleobase umfasst.
- Modifizierte siRNA nach einem der vorhergehenden Ansprüche, wobei jeder Strang 12-35 Monomere umfasst.
- Pharmazeutische Zusammensetzung, umfassend die modifizierte siRNA nach einem der Ansprüche 1-13 und ein pharmazeutisch unbedenkliches Verdünnungsmittel, Träger oder Adjuvans.
- Modifizierte siRNA nach einem der Ansprüche 1-13 zur Verwendung als Arzneimittel.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200400145 | 2004-01-30 | ||
PCT/DK2004/000192 WO2004083430A2 (en) | 2003-03-21 | 2004-03-22 | SHORT INTERFERING RNA (siRNA) ANALOGUES |
DKPA200401079 | 2004-07-08 | ||
PCT/DK2005/000062 WO2005073378A1 (en) | 2004-01-30 | 2005-01-28 | MODIFIED SHORT INTERFERING RNA (MODIFIED siRNA) |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1713912A1 EP1713912A1 (de) | 2006-10-25 |
EP1713912B1 true EP1713912B1 (de) | 2013-09-18 |
Family
ID=36997281
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05700612.4A Active EP1713912B1 (de) | 2004-01-30 | 2005-01-28 | Modifizierte sirna (short interfering rna) |
Country Status (4)
Country | Link |
---|---|
US (1) | US20080249039A1 (de) |
EP (1) | EP1713912B1 (de) |
DK (1) | DK1713912T3 (de) |
WO (1) | WO2005073378A1 (de) |
Families Citing this family (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE443765T1 (de) | 2003-03-21 | 2009-10-15 | Santaris Pharma As | Analoga kurzer interferierender rna (sirna) |
US20100041738A1 (en) * | 2005-06-20 | 2010-02-18 | Avaris Ab | Hybridization-stabilizing construct |
US20090018097A1 (en) * | 2005-09-02 | 2009-01-15 | Mdrna, Inc | Modification of double-stranded ribonucleic acid molecules |
AU2007209481B2 (en) * | 2006-01-27 | 2012-01-12 | Roche Innovation Center Copenhagen A/S | LNA modified phosphorothiolated oligonucleotides |
JP5244087B2 (ja) * | 2006-03-23 | 2013-07-24 | サンタリス ファーマ アー/エス | 低分子内部セグメント化干渉rna |
ES2603379T3 (es) | 2006-10-09 | 2017-02-27 | Roche Innovation Center Copenhagen A/S | Compuestos antagonistas de ARN para la modulación de PCSK9 |
EP2195428B1 (de) | 2007-09-19 | 2013-12-11 | Applied Biosystems, LLC | Sirna-sequenz-unabhängige modifikationsformate zur verringerung von das ziel verfehlenden phänotypischen effekten bei rnai und stabilisierte formen davon |
AU2009273878A1 (en) * | 2008-07-25 | 2010-01-28 | Alnylam Pharmaceuticals, Inc. | Enhancement of siRNA silencing activity using universal bases or mismatches in the sense strand |
US8957038B2 (en) | 2009-07-15 | 2015-02-17 | Medtronic, Inc. | Treatment of neurological disorders |
WO2011009697A1 (en) | 2009-07-21 | 2011-01-27 | Santaris Pharma A/S | Antisense oligomers targeting pcsk9 |
EP2544703A4 (de) | 2010-03-12 | 2013-09-18 | Brigham & Womens Hospital | Verfahren zur behandlung von gefässentzündungserkrankungen |
PT2561078T (pt) | 2010-04-23 | 2018-12-03 | Cold Spring Harbor Laboratory | Sharn com uma conceção estrutural inovadora |
US20140031250A1 (en) | 2010-10-07 | 2014-01-30 | David Tsai Ting | Biomarkers of Cancer |
US9920317B2 (en) | 2010-11-12 | 2018-03-20 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
AU2011325956B2 (en) | 2010-11-12 | 2016-07-14 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
US9045749B2 (en) | 2011-01-14 | 2015-06-02 | The General Hospital Corporation | Methods targeting miR-128 for regulating cholesterol/lipid metabolism |
MX2014004516A (es) | 2011-10-11 | 2015-01-16 | Brigham & Womens Hospital | Micro-arns en trastornos neurodegenerativos. |
EP2850188A4 (de) | 2012-05-16 | 2016-01-20 | Rana Therapeutics Inc | Zusammensetzungen und verfahren zur modulierung der expression der hämoglobin-genfamilien |
CN104583401A (zh) | 2012-05-16 | 2015-04-29 | Rana医疗有限公司 | 用于调节atp2a2表达的组合物和方法 |
EA201492123A1 (ru) | 2012-05-16 | 2015-10-30 | Рана Терапьютикс, Инк. | Композиции и способы для модулирования экспрессии семейства генов smn |
US10837014B2 (en) | 2012-05-16 | 2020-11-17 | Translate Bio Ma, Inc. | Compositions and methods for modulating SMN gene family expression |
EA201492116A1 (ru) | 2012-05-16 | 2015-05-29 | Рана Терапьютикс, Инк. | Композиции и способы для модулирования экспрессии mecp2 |
CN104540946A (zh) | 2012-05-16 | 2015-04-22 | Rana医疗有限公司 | 用于调节utrn表达的组合物和方法 |
WO2013184209A1 (en) | 2012-06-04 | 2013-12-12 | Ludwig Institute For Cancer Research Ltd. | Mif for use in methods of treating subjects with a neurodegenerative disorder |
PL2920304T3 (pl) | 2012-11-15 | 2019-07-31 | Roche Innovation Center Copenhagen A/S | Koniugaty oligonukleotydowe |
PT3013959T (pt) | 2013-06-27 | 2020-02-04 | Roche Innovation Ct Copenhagen As | Oligómeros antissentido e conjugados dirigidos para pcsk9 |
WO2015200697A1 (en) | 2014-06-25 | 2015-12-30 | The General Hospital Corporation | Targeting human satellite ii (hsatii) |
WO2016033472A1 (en) | 2014-08-29 | 2016-03-03 | Children's Medical Center Corporation | Methods and compositions for the treatment of cancer |
CA2966044A1 (en) | 2014-10-30 | 2016-05-06 | The General Hospital Corporation | Methods for modulating atrx-dependent gene repression |
WO2016137937A1 (en) * | 2015-02-24 | 2016-09-01 | Dcb-Usa Llc | Short interfering rna for treating cancer |
WO2016149455A2 (en) | 2015-03-17 | 2016-09-22 | The General Hospital Corporation | The rna interactome of polycomb repressive complex 1 (prc1) |
US10961532B2 (en) | 2015-04-07 | 2021-03-30 | The General Hospital Corporation | Methods for reactivating genes on the inactive X chromosome |
WO2016210241A1 (en) | 2015-06-26 | 2016-12-29 | Beth Israel Deaconess Medical Center, Inc. | Cancer therapy targeting tetraspanin 33 (tspan33) in myeloid derived suppressor cells |
WO2017066712A2 (en) | 2015-10-16 | 2017-04-20 | The Children's Medical Center Corporation | Modulators of telomere disease |
WO2017066796A2 (en) | 2015-10-16 | 2017-04-20 | The Children's Medical Center Corporation | Modulators of telomere disease |
WO2017087708A1 (en) | 2015-11-19 | 2017-05-26 | The Brigham And Women's Hospital, Inc. | Lymphocyte antigen cd5-like (cd5l)-interleukin 12b (p40) heterodimers in immunity |
JP7033072B2 (ja) | 2016-02-25 | 2022-03-09 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッド | Smoc2を標的化する線維症のための治療方法 |
EP3532638A4 (de) | 2016-10-31 | 2020-07-29 | University of Massachusetts | Targeting von microrna-101-3p in der krebstherapie |
EP3612232A1 (de) | 2017-04-21 | 2020-02-26 | The Broad Institute, Inc. | Gezielte abgabe an beta-zellen |
WO2019036375A1 (en) | 2017-08-14 | 2019-02-21 | Sanford Burnham Prebys Medical Discovery Institute | CARDIOGENIC MESODERMA TRAINING REGULATORS |
US11413288B2 (en) | 2017-11-01 | 2022-08-16 | Dana-Farber Cancer Institute, Inc. | Methods of treating cancers |
US20210292766A1 (en) | 2018-08-29 | 2021-09-23 | University Of Massachusetts | Inhibition of Protein Kinases to Treat Friedreich Ataxia |
WO2020171889A1 (en) | 2019-02-19 | 2020-08-27 | University Of Rochester | Blocking lipid accumulation or inflammation in thyroid eye disease |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US6506559B1 (en) * | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
DE19956568A1 (de) * | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
US20020068709A1 (en) * | 1999-12-23 | 2002-06-06 | Henrik Orum | Therapeutic uses of LNA-modified oligonucleotides |
WO2003070918A2 (en) * | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | Rna interference by modified short interfering nucleic acid |
WO2002081628A2 (en) * | 2001-04-05 | 2002-10-17 | Ribozyme Pharmaceuticals, Incorporated | Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies |
KR20080023768A (ko) * | 2000-03-30 | 2008-03-14 | 화이트헤드 인스티튜트 포 바이오메디칼 리서치 | Rna 간섭의 rna 서열 특이적인 매개체 |
CZ302719B6 (cs) * | 2000-12-01 | 2011-09-21 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Izolovaná molekula dvouretezcové RNA, zpusob její výroby a její použití |
EP2221377B2 (de) * | 2002-02-01 | 2017-05-17 | Life Technologies Corporation | Doppelsträngige Oligonukleotide |
MXPA05001355A (es) * | 2002-08-05 | 2005-09-30 | Atugen Ag | Formas nuevas adicionales de moleculas de arn de interferencia. |
ATE443765T1 (de) * | 2003-03-21 | 2009-10-15 | Santaris Pharma As | Analoga kurzer interferierender rna (sirna) |
US20040224405A1 (en) * | 2003-05-06 | 2004-11-11 | Dharmacon Inc. | siRNA induced systemic gene silencing in mammalian systems |
NZ555644A (en) * | 2004-11-09 | 2009-04-30 | Santaris Pharma As | Potent LNA oligonucleotides for the inhibition of HIF-1A expression |
DE102005030529A1 (de) * | 2005-06-30 | 2007-01-04 | Deutsche Telekom Ag | Verfahren und System zur Verteilung von Konfigurationen auf Clientrechner |
AU2007209481B2 (en) * | 2006-01-27 | 2012-01-12 | Roche Innovation Center Copenhagen A/S | LNA modified phosphorothiolated oligonucleotides |
-
2005
- 2005-01-28 DK DK05700612.4T patent/DK1713912T3/da active
- 2005-01-28 EP EP05700612.4A patent/EP1713912B1/de active Active
- 2005-01-28 US US10/587,775 patent/US20080249039A1/en not_active Abandoned
- 2005-01-28 WO PCT/DK2005/000062 patent/WO2005073378A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
DK1713912T3 (da) | 2013-12-16 |
EP1713912A1 (de) | 2006-10-25 |
US20080249039A1 (en) | 2008-10-09 |
WO2005073378A1 (en) | 2005-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1713912B1 (de) | Modifizierte sirna (short interfering rna) | |
US9738894B2 (en) | Short interfering RNA (siRNA) analogues | |
EP1984382B1 (de) | Lna-modifizierte phosphorothiolierte oligonukleotide | |
ES2344566T3 (es) | Compuestos oligomericos para la modulacion de bcl-2. | |
US20080188432A1 (en) | Oligomeric compounds for the modulation ras expression | |
WO2007031091A2 (en) | Rna antagonist compounds for the modulation of p21 ras expression | |
JP2021524450A (ja) | マイクロrna関連疾患の処置のための薬学的組成物 | |
EP1592794A2 (de) | Oligomere verbindungen modulation der expression von thioredoxin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20060821 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20071107 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: SANTARIS PHARMA A/S |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: KOCH, TROELS Inventor name: LIANG, ZICAI Inventor name: WAHLESTEDT, CLAES Inventor name: RUM, HENRIK Inventor name: ELM N, JOACIM |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Ref document number: 602005041254 Country of ref document: DE Free format text: PREVIOUS MAIN CLASS: C12N0015110000 Ipc: C12N0015113000 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: SANTARIS PHARMA A/S |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C12N 15/113 20100101AFI20121221BHEP |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20130408 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: KOCH, TROELS Inventor name: ELMEN, JOACIM Inventor name: ORUM, HENRIK Inventor name: WAHLESTEDT, CLAES Inventor name: LIANG, ZICAI |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 632831 Country of ref document: AT Kind code of ref document: T Effective date: 20131015 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602005041254 Country of ref document: DE Effective date: 20131114 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 Effective date: 20131209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130710 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: VDEP Effective date: 20130918 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 632831 Country of ref document: AT Kind code of ref document: T Effective date: 20130918 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20131219 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140118 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602005041254 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140120 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20140619 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: LU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140128 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602005041254 Country of ref document: DE Effective date: 20140619 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140131 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140131 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140128 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 12 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130918 Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20050128 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 13 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 14 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 602005041254 Country of ref document: DE Representative=s name: D YOUNG & CO LLP, DE |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231219 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20231219 Year of fee payment: 20 Ref country code: DK Payment date: 20231219 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20231219 Year of fee payment: 20 |